Researchers May Have Found How Cerebral Malaria Attacks the Brain
The authors may have also discovered a potential therapeutic target for the complication.
Most clinicians know that cerebral malaria, a complication associated with the all-too-common mosquito-borne virus that affects much of the developing world, can be deadly; however, relatively little is known about exactly how the disease attacks the human brain.
That may be changing.
Using mouse models, the authors of a study published online on December 1, 2016 by the journal PLOS Pathogens, demonstrated that cytotoxic T-cells attack cerebral blood vessels, leading to swelling in the brain. They believe that their findings mirror how cerebral malaria affects the human brain. The complication is associated with Plasmodium falciparum malaria, the most dangerous form of the virus. Exact figures on its incidence are not available; however, it is believed that more than 500,000 children develop cerebral malaria annually in Africa alone, and that it causes as many as 1 million deaths worldwide each year. It is fatal in as many as 30% of the people it afflicts. Sufferers typically experience seizures and may lapse into a coma.
To learn more about this troubling complication, the team of researchers from the National Institutes of Health (NIH) used intravital 2-photon microscopy to assess the immune cell activity in the brains of mice infected with Plasmodium berghei ANKA, which causes a neurological disease called experimental cerebral malaria (ECM) that has characteristics similar to those of human cerebral malaria. They found that cytotoxic T-cells—specifically, myelomonocytic cells and parasite-specific CD8+ T-cells—aggregated adjacent to, and “interacted” with, blood vessels in the brains of infected mice, causing vascular leakage. This vascular leakage caused the brains of the infected mice to swell, killing the neurons that managed cardiovascular functions.
To get to this point, the authors noted that the myelomonocytic cells in the infected mice “participated in the removal of parasitized red blood cells” from blood vessels, while “the majority of disease-inducing parasite-specific CD8+ T-cells interacted with the lumen of brain vascular endothelial cells, where they were observed surveying, dividing, and arresting in a cognate peptide-MHC I dependent manner.” In perhaps the most important observation, the authors also found that interferon-γ played an important role in this disease activity; it activated the cerebral endothelial cells, which are needed to upregulate adhesion and antigen-presenting molecules.
In addition to providing new insights into the pathophysiology of cerebral malaria, the authors of the PLOS Pathogens paper may have also identified a potential therapeutic target for the complication. In their observations of disease activity in mouse models, they demonstrated that treatment with an anti-adhesion molecule (LFA-1 / VLA-4)—which kept the T-cells from adhering the cerebral blood vessels—“prevented fatal disease by rapidly displacing luminal CD8+ T cells from cerebrovascular [endothelial cells] without affecting extravascular T cells.”
The authors did not respond to requests for comment. However, in their concluding remarks, they wrote, “[W]e have provided the first in vivo evidence detailing how CD8+ T cells cause ECM… and [we]… hypothesize that CD8+ T cells use a noncytopathic mechanism to disrupt cerebrovascular [endothelial cell] tight junctions. This signifies that the disease is reversible up to the point when severe edema gives rise to cerebral herniation and death of brainstem neurons (an irreversible event). The reversibility of the disease is demonstrated by the effectiveness of late anti-adhesion molecule blockade. Because many patients with [cerebral malaria] likely arrive in the hospital with active [blood-brain barrier] breakdown, effective therapies need to target parasite acquisition by [endothelial cells] and subsequent CD8+ T cell engagement. In addition to anti-malarial drugs and supportive care, consideration should also be given to therapeutics that interfere with T cell function/metabolism or that temporarily displace these cells from cerebral vasculature.”
Brian P. Dunleavy is a medical writer and editor based in New York. His work has appeared in numerous healthcare-related publications. He is the former editor of Infectious Disease Special Edition.
